Elucidation of the Signaling Pathways Underlying Bisphenol A's Arrhythmogenic Effects in Female Hearts

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 338-354-Physiological Impacts of Endocrine Disrupting Chemicals
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-345
Xiaoqian Gao*1, Qian Liang2, Yamei Chen2 and Hong-Sheng Wang3
1University of Cincinnati, Cincinnati, OH, 2University of Cincinnati, 3Department of Pharmacology and C, Cincinnati, OH
Bisphenol A (BPA) is an estrogenic endocrine disrupting chemical, which has been shown to have a wide human exposure and implicated to be potentially harmful to human health. Epidemiologic studies have demonstrated that higher urine BPA concentrations are associated with cardiovascular diseases in humans. Previously we reported that low-doses of BPA rapidly promoted arrhythmias in female, but not male rat hearts through ERb activation and alteration of Ca2+ handling. In particular, BPA increased spontaneous Ca2+ leak from the Sarcoplasmic reticulum (SR), and also increased SR Ca2+ reuptake as well as SR Ca2+ load. However, how the activation of ERb led to the alteration of Ca2+ cycling was unknown. The signaling pathways underlying BPA’s arrhythmogenic effects were still not fully understood.

We investigated how BPA treatment on female rat myocytes affected two key cardiac Ca2+ handling proteins: Ryanodine receptor (RyR) and phospholamban (PLN). RyR mediates Ca2+ release from SR while PLN regulates SR Ca2+ reuptake process, and both proteins could be phosphorylated by Kinases to increase their activities and alter Ca2+ cycling. Using western blots we found that under BPA treatment, RyR phosphorylation increased within 5 minutes at PKA’s site (RyR2808), but not CAMKII’s site (RyR2814); while PLN phosphorylation increased with similar time course at CAMKII’s site (PLN17), but not PKA’s site (PLN16). The increases of phosphorylation on both RyR and PLN are diminished with the treatment of ERb blocker, but not ERa blocker. When blockers for PKA or CAMKII were applied together with BPA, the effect of BPA on RyR and PLN phosphorylation were completely abolished. We performed Ca2+ sparks study to examine the SR Ca2+ release from RyR, and we observed that PKA blockers completely blunted Ca2+ spark increase induced by BPA. Then we measured the “triggered activities” on myocytes through both after-contraction and after-transient experiments, which are direct indicators for the arrhythmogenesis on the myocyte. We found that both PKA and CAMKII blockers completely abolished the “triggered activities” induced by BPA, which pointed to the important roles of these two kinases in the arrhythmogenic effects of BPA in the female heart.

In conclusion, our results demonstrate that BPA promotes cardiac arrhythmias via activation of PKA and CAMKII signaling pathways, and altering the phosphorylation of key cardiac Ca2+ handling proteins.

Nothing to Disclose: XG, QL, YC, HSW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by National Institute of Health grants R01-ES017262, R21-HL084539 (HSW).